Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid‐β, α‐synuclein, and prions, that can activate inflammasomes. ...Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host‐derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin (IL)‐1β and IL‐18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS‐resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome‐targeted strategies that may potentially treat these diseases.
What is the role of inflammasomes in degenerative diseases like Alzheimer's, Parkinson's, Huntington's, prion diseases, ALS, MS, stroke, TBI and spinal cord injury? Current understandings are here discussed along with potential inflammasome‐targeted strategies to treat these diseases.
Epidermal keratinocytes provide an essential structural and immunological barrier forming the first line of defense against potentially pathogenic microorganisms. Mechanisms regulating barrier ...integrity and innate immune responses in the epidermis are important for the maintenance of skin immune homeostasis and the pathogenesis of inflammatory skin diseases. Here, we show that epidermal keratinocyte-restricted deficiency of the adaptor protein FADD (FADD
E-KO) induced severe inflammatory skin lesions in mice. The development of skin inflammation in FADD
E-KO mice was triggered by RIP kinase 3 (RIP3)-mediated programmed necrosis (termed necroptosis) of FADD-deficient keratinocytes, which was partly dependent on the deubiquitinating enzyme CYLD and tumor necrosis factor (TNF)-TNF receptor 1 signaling. Collectively, our findings provide an in vivo experimental paradigm that regulation of necroptosis in keratinocytes is important for the maintenance of immune homeostasis and the prevention of chronic inflammation in the skin.
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► Epidermal FADD deficiency triggers keratinocyte necrosis and skin inflammation in mice ► RIP3-mediated keratinocyte necroptosis triggers skin inflammation in FADDEKO mice ► Keratinocyte necrosis and inflammation in FADDEKO mice partly depend on CYLD and TNFR ► MyD88 signaling contributes to skin inflammation in FADDEKO mice
Microglia are the resident macrophages of the central nervous system (CNS). They have important physiological functions in maintaining tissue homeostasis but also contribute to CNS pathology. ...Microglia respond to changes in the microenvironment, and the resulting reactive phenotype can be very diverse, with both neuroinflammatory and neuroprotective properties, illustrating the plasticity of these cells. Recent progress in understanding the autoimmune neuroinflammatory disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis suggests major roles for microglia in the disease, which have drastically changed our view on the function of microglia in MS.
Microglia are shaped by their ontogeny and the specific CNS microenvironment, defining the functional plasticity of these cells. Microglia can respond to different types of stimuli, including exogenous infectious pathogens as well as injurious self-proteins, and initiate a neuroinflammatory response.
In MS, microglia alter their transcriptional profile and become ‘disease-associated microglia’ (DAM). DAM cells in EAE display a profuse inflammatory phenotype, in contrast to other neurodegenerative diseases.
In MS and EAE, microglia induce different effector functions that can be both neuroprotective and detrimental. Currently, it is believed that the initial response of microglia is beneficial, aiming to resolve the insult, but that chronic activation of microglia contributes to neurodegeneration.
Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the ...second messenger cGAMP, and the adaptor molecule STING. Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62‐deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens. In the absence of p62, STING failed to traffic to autophagy‐associated vesicles. Thus, DNA sensing induces the cGAS‐STING pathway to activate TBK1, which phosphorylates IRF3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response.
Synopsis
Stimulation of the cGAS‐STING pathway by cytosolic DNA leads to STING ubiquitination and degradation. The downstream cGAS‐STING kinase TBK1 also phosphorylates the selective autophagy receptor p62, which in turn directs STING for degradation by autophagy.
Abrogation of autophagy severely impaired DNA‐stimulated STING degradation.
p62 is essential for DNA‐stimulated STING degradation.
Cells lacking p62 have elevated interferon responses to cytoplasmic DNA and DNA pathogens.
TBK1 phosphorylates p62, which promoted STING degradation and regulation of the pathway.
Stimulation of the cGAS‐STING innate immunity pathway by cytosolic DNA leads to TBK1‐mediated phosphorylation of the selective autophagy receptor p62, directing ubiquitinated STING to autophagosomes and degradation.
Monocytes/macrophages are critical in orchestrating the tissue-repair response. However, the mechanisms that govern macrophage regenerative activities during the sequential phases of repair are ...largely unknown. In the present study, we examined the dynamics and functions of diverse monocyte/macrophage phenotypes during the sequential stages of skin repair. By combining the analysis of a new CCR2-eGFP reporter mouse model with conditional mouse mutants defective in myeloid cell–restricted CCR2 signaling or VEGF-A synthesis, we show herein that among the large number of inflammatory CCR2+Ly6C+ macrophages that dominate the early stage of repair, only a small fraction strongly expresses VEGF-A that has nonredundant functions for the induction of vascular sprouts. The switch of macrophage-derived VEGF-A during the early stage of tissue growth toward epidermal-derived VEGF-A during the late stage of tissue maturation was critical to achieving physiologic tissue vascularization and healing progression. The results of the present study provide new mechanistic insights into CCR2-mediated recruitment of blood monocyte subsets into damaged tissue, the dynamics and functional consequences of macrophage plasticity during the sequential repair phases, and the complementary role of macrophage-derived VEGF-A in coordinating effective tissue growth and vascularization in the context of tissue-resident wound cells. Our findings may be relevant for novel monocyte-based therapies to promote tissue vascularization.
A20 also known as TNFAIP3 (tumour necrosis factor α-induced protein 3) restricts and terminates inflammatory responses through modulation of the ubiquitination status of central components in NF-κB ...(nuclear factor κB), IRF3 (interferon regulatory factor 3) and apoptosis signalling cascades. The phenotype of mice with full or conditional A20 deletion illustrates that A20 expression is essential to prevent chronic inflammation and autoimmune pathology. In addition, polymorphisms within the A20 genomic locus have been associated with multiple inflammatory and autoimmune disorders, including SLE (systemic lupus erythaematosis), RA (rheumatoid arthritis), Crohn's disease and psoriasis. A20 has also been implicated as a tumour suppressor in several subsets of B-cell lymphomas. The present review outlines recent findings that illustrate the effect of A20 defects in disease pathogenesis and summarizes the identified A20 polymorphisms associated with different immunopathologies.
Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (
Tnfaip3) determines the activation threshold of DCs, via control of canonical ...NF-κB activation.
Tnfaip3
fl/fl
Cd11c-
cre
+ mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly—features of systemic lupus erythematosus—and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in
TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.
► A20 deficiency in DCs causes systemic autoimmunity ► A20-deficient DCs stimulate plasma cell conversion in the absence of T cells ► A20 is proapoptotic in DCs ► A20-deficient DCs better capture and present apoptotic cells
Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is ...considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.
Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2+Ly6Chi monocytes. However, the mechanisms driving tumor cell ...extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2+ endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2−/− mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.
► Tumor-cell derived CCL2 controls vascular permeability, extravasation, and metastasis ► Endothelial CCR2 expression is necessary and sufficient for extravasation/ metastasis ► Activation of JAK2-Stat5 and p38MAPK signaling via CCR2 induce vascular permeability ► CCL2 expression levels correlate with metastatic potential of UICC IV colon carcinoma
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